Emergency Contraception

Emergency contraception (EC), also known as post-coital contraception and the morning-after pill, refers to the use of drugs or a device as an emergency measure to prevent pregnancy. Women, who have had recent unprotected intercourse, including those who have had a failure of another method of contraception, are potential candidates for this intervention. It is intended for occasional or back-up use, not as a primary contraceptive method for routine use. Women seeking emergency contraception typically are younger than 25 years, have never been pregnant, and have used some form of contraception in the past. Emergency contraceptive pills are now available in many countries, but have failed to have the desired impact on unwanted pregnancy rates. Although family planning enhances efforts to improve health and accelerate development, shifting international priorities, health sector reform, the human immunodeficiency virus (HIV) crisis, and other factors have affected its importance in recent years. Traditional beliefs favoring high fertility, religious barriers, and lack of male involvement have weakened family planning interventions. The combination of these factors has led to low contraceptive use, high fertility rates in many countries, and high unmet needs for family planning throughout the region (1). Family planning advocates must take action to change this situation. Family planning, considered an essential component of primary health care and reproductive health, plays a major role in reducing maternal and newborn morbidity and mortality and transmission of HIV. It contributes to the achievement of the Millennium Development Goals (MDGs) and the targets of the Health-for-All Policy for the 21st century in the African Region: Agenda 2020. Many health care providers, federal and state policy makers, and reproductive rights activists have been engaged in campaigns to improve the public's awareness of emergency contraception.

The purpose of this document is to address the progestin-only and combined oral contraceptive methods (which are the most frequently used methods and also approved by the U.S. Food and Drug Administration [FDA] specifically for emergency contraception) and briefly address the use of the copper intrauterine device (IUD) because of its use as both long-term contraception and emergency contraception. Recently approved 5-day emergency contraceptive (ulipristal acetate) by FDA is explored. Future possibilities are also reviewed. To maximize effectiveness, women should be educated about the availability of emergency contraception methods. Clinical evaluation is indicated for women who have used emergency contraceptive if menses are delayed by a week or more after the expected time or if lower abdominal pain or persistent irregular bleeding develops. Increasing emergency contraception (EC) awareness and knowledge are important priorities in the effort to prevent unwanted and unintended pregnancy.

Introduction

Although oral EC was first described in the medical literature decades ago, in 1998 the U.S. FDA approved the first dedicated product for EC. Many women are unaware of the existence of emergency contraceptive methods, misunderstand its use and safety, or do not use it when a need arises. Research on the post-coital use of contraceptive steroids began in the 1960s. The first oral regimen, which used a widely available brand of combined estrogen-progestin oral contraceptive pills, was published in 1974 by Yuzpe and colleagues. Research on progestin-only regimens for occasional post-coital use by women having infrequent intercourse also began about that time. EC should be offered or made available to women who have had unprotected or inadequately protected sexual intercourse and who do not desire pregnancy. The World Health Organization's "Medical Eligibility Criteria for Contraceptive Use" include no conditions in which the risks of EC use outweigh the benefits (2). These criteria note specifically that women with previous ectopic pregnancy, cardiovascular disease, migraines, or liver disease and women who are breastfeeding may use EC. Therefore, EC should be made available to women with contraindications to the use of conventional oral contraceptive preparations. Reproductive-aged women who are victims of sexual assault should always be offered EC.

Hormonal EC is a well established contraceptive method, recommended to all women, although the effects on hemostasis are not fully evaluated. The aim of this study (3) was to evaluate whether exposure to EC has effects on well established cardiovascular risk factors, and also to examine whether differences exist between two EC treatments. In a prospective randomized cross over design 11 women used two different EC methods, one with ethinyl estradiol and levonorgestrel (EE-EC) and one with levonorgestrel only (LNG-EC). Plasma concentrations of hemostatic factors (APC resistance, antithrombin, fibrinogen, prothrombin fragment 1 + 2, free protein S, factor VII and PAI-1), sex-hormone-binding globulin (SHBG), the apolipoprotein (apo)B/apoA1 ratio and C-reactive protein (CRP) were followed frequently during the following 48 hours. A rapid hemostatic activation was induced with both treatments, although more pronounced with EE-EC. Already two hours after EC, the plasma concentrations of hemostatic parameters and SHBG were significantly different from baseline concentrations. An ETP-based APC-resistance method showed increased APC resistance with EE-EC and decreased APC resistance with LNG-EC. The ApoB/ApoA1 ratio was affected in a favorable direction with EE-EC. CRP increased slightly regardless of treatment (3). Even a very short exposure to exogenous sex hormones causes prompt effects on hepatic protein synthesis and the coagulation system. This must be taken into consideration whenever exogenous steroid hormones are administered, especially to individuals with a genetic predisposition to thrombosis or transiently disturbed hemostasis.

Barriers to Use

Surveys have documented that a large number of women are unaware of the existence of EC or have insufficient knowledge to allow them to use it effectively. The results of survey of Californians between the ages of 15 and 44 years indicate that 35% of the participants did not know of any way to prevent becoming pregnant after sex, and 43% were not aware the EC is available in the United States (4). In a 2007 study, few women who received information about EC remembered discussing it after 12-months (5). Additionally, many healthcare providers are poorly informed about this method. In a 2008 U.S. Survey, almost one in five healthcare providers was reluctant to provide education on the subject to sexually active adolescents (6). Finally, three studies evaluating female sexual victims seen in emergency departments indicated that only 21-50% of eligible women received EC (6). More studies to evaluate barriers to use in specific populations are needed, so that appropriate policy interventions can be implemented. Availability of EC has improved since it was approved for over-the-counter access for those 17 years and older. A study of 1,087 pharmacies in Philadelphia, Boston, and Atlanta in USA found that even when availability was limited to behind-the-counter status (i.e., being available without prescription, but only after intervention by a pharmacist) the percentage of pharmacies unable to provide Plan B within 24 hours decreased from 23% in 2005 to 8% in 2007 (7). However, previously documented barriers such as limited access to EC through pharmacies, student health centers, urgent care centers, and other sources remain for women younger than 17 years. Consequently, healthcare providers need to pay particular attention to barriers for EC use for this at-risk population.

Even when knowledge of this type of contraceptive is higher, use often remains fairly low, as in the United Kingdom of Great Britain and Northern Ireland, where 91% of women had heard of "the morning-after-pill" but only 7% had used it in the past year. One reason for low correct use of EC is the very poor basic understanding of fertility, contraception and pregnancy risk that seems widespread in both developed and developing countries. In France, a survey of women seeking abortion indicated that more than half were unaware of their pregnancy risk at the time that they became pregnant or could not identify the specific act of intercourse that led to the pregnancy; only a minority of women used EC. In the United Kingdom, a study of abortion and prenatal care clients showed that EC were used by only one in ten women who definitely did not wish to become pregnant, and even fewer used the method every time they were at risk of pregnancy (8). Knowledge about EC continues to be an important barrier in much of the world. This post-coital contraceptive method is still relatively unknown in many countries according to data from Demographic and Health surveys (9). A 2007 survey of adolescents in New York City Schools revealed that fewer than half of these young people had heard about EC, despite extensive public outreach and media publicity surrounding their over-the-counter status in the USA (9).

Regimens of Emergency Contraception Commonly Used in USA

There are two most commonly used oral emergency contraception regimens:

The progestin-only regimen -- which consists of a total of 1.5 mg of levonorgestrel. The two levonorgestrel-only regimens available in the United States, specifically dedicated for EC, are the single-dose protocol and the two-dose protocol. Two-dose regimen -- 2 tablets, each containing 0.75 mg levonorgestrel taken 12 hours apart; Single-dose regimen -- 1 tablet, containing 1.5 mg levonorgestrel.

The combined estrogen-progestin regimen can be formulated from a variety of standard oral contraceptives, although data exist only for regimens containing levonorgestrel, norgestrel (levonorgestrel plus an equal amount of the inactive enantiomer dextronorgestrel), and norethindrone. The two 0.75 mg doses of levonorgestrel-only regimen are equally effective if taken 12-24 hours apart, which may improve adherence (10). The single-dose 1.5 mg levonorgestrel-only regimen is as effective as the two-dose regimen taken 12 hours apart (10). Other regimens have been proposed for use as EC, including single-dose 30 mg ulipristal acetate tablet, which has been shown to be effective in preventing pregnancy up to 120 hours after unprotected intercourse.

Initiation of Emergency Contraception

No clinical examination or pregnancy testing is necessary before provision or prescription of EC is provided. EC should be offered or made available any time unprotected or inadequately protected intercourse occurs and the patient is concerned that she is at risk for an unwanted pregnancy. EC should not be withheld or delayed in order to test for pregnancy, nor should be denied because the unprotected coital act may not have occurred on a fertile day of the menstrual cycle. Treatment should be initiated as soon as possible after unprotected or inadequately protected intercourse to maximize efficacy, which decreases with time. However, a few studies have not observed the time effect with the combined estrogen-progestin regimen (11). Because earlier studies demonstrated that both regimens are effective when initiated up to 72 hours after intercourse, product package instructions advise use only within that time frame. More recent studies have shown that EC is still moderately effective when the first dose is taken up to 5 days after intercourse and may be made available to patients who request it up to 5 days after intercourse (11)(12).

IUD for Emergency Contraception: Use of copper IUD for emergency contraception, first reported in 1976, has been studied in prospective cohort trial with pregnancy rates of 0-0.1% (13). In these trials, the IUD was inserted up to 5 days after unprotected intercourse. A more recent report of 1,013 women who underwent insertion of a copper IUD for EC, including 170 nulliparous women, found a pregnancy rate of 0.2% (14). One advantage of using the copper IUD for EC is that it can be retained for continued long-term contraception. The same study found 86% of parous women and 80% of nulliparous women maintained the IUD for contraception. The copper IUD is appropriate for EC in women who meet standard criteria of IUD insertion and is most effective if inserted within 5 days after unprotected intercourse. This method is particularly useful for women who desire long-term contraception use. The levonorgestrel-releasing intrauterine system is not effective as an emergency contraception (14).

Access

The universal availability of dedicated EC products has been controversial, and these drugs are currently separated into over-the-counter and prescription-only access based on age. EC is available without a prescription for individuals (men or women) age 17 and older; proof of age is required (government issued photo or non-photo identification). Adolescents 16 years and under still require a prescription; however, some states allow specially trained pharmacists to dispense emergency contraception to these women as long as the pharmacist has a standing agreement with a physician to provide these prescriptions as needed. Limited data suggest adolescents use EC appropriately and tolerate the drug about as well as adults (15). Clinicians should be aware of the potential barriers to access and should encourage women to obtain emergency contraceptives in advance of a need for them. In 1973, Congress passed the Church Amendment which allowed health care providers (physicians, nurses, pharmacists, etc.) to cite religious grounds for refusing to provide abortion or sterilization services. Over time, refusal clauses have passed in most states and have been extended to include contraception and emergency contraception, assisted reproductive technologies, human embryonic or fetal research, and stem cell research. Ideally, professionals who object to providing such services should forewarn their patients and refer them promptly so that their health is not threatened, or care compromised. Providing advance EC to adolescents is not associated with more unprotected intercourse or less condom or hormonal contraception use. In this study, the first month after enrollment, adolescents provided with advance EC were nearly twice as likely to use it and began EC sooner, when it is known to be more effective (16).

Mechanism of Action

No single mechanism of action has been established for EC; rather, the mode of action varies according to the day of the menstrual cycle on which intercourse occurs and EC is administered. Both the combined regimen and the levonorgestrel-only regimen have been shown to inhibit or delay ovulation (17). Earlier studies documented histologic and biochemical changes in the endometrium after administration of the combined regimen, suggesting that emergency contraceptives may alter the receptiveness of the endometrium and inhibit implantation of a fertilized egg. However, several more recent studies have not supported these findings, and the endometrial changes that have been observed may not be sufficient to prevent implantation. Interference with sperm transport or penetration and impairment of corpus luteum function have been proposed as other possible mechanism of action (18), but there is no direct clinical evidence to support these theories.

EC is sometimes confused with medical abortion. However, whereas medical abortion is used to terminate an existing pregnancy, EC is effective only before a pregnancy is established. EC can prevent pregnancy during the 5 or more days between intercourse and implantation of a fertilized egg, but it is ineffective after implantation. Studies of high-dose oral contraceptives indicate that EC confers no increased risk to an established pregnancy or harm to a developing embryo (19). No studies have specifically investigated adverse effects of exposure to EC during early pregnancy. However, numerous studies of the teratogenic risk of contraception during early use of oral contraceptives (including older, higher-dose preparations) have found no increase in risk to either the pregnant woman or the developing fetus (19). Existing data indicate that use of EC does not increase the chance that a subsequent pregnancy will be ectopic (19). EC like all other contraceptives, actually reduces the absolute risk of ectopic pregnancy by preventing pregnancy.

Effectiveness of Emergency Contraception

For EC, efficacy is defined as the number of pregnancies observed after treatment divided by the estimated number of pregnancies that would occur without treatment. When this proportion is subtracted from one, the resulting statistic is the "prevented fraction", which represents the estimated percentage of cases averted by the treatment. Reported figures on the efficacy of EC vary considerably and are imprecise. Levonorgestrel 1.5 mg (two split doses or a single dose) and low and mid-doses (25-50 mg) of mifepristone offer high efficacy with an acceptable side-effect profile. Single dose simplifies the use of levonorgestrel for emergency contraception without an increase in side-effects (14). However, mifepristone might delay the following menstruation, which could increase anxiety, particularly in higher doses. The Yuzpe regimen could be used if levonorgestrel or mifepristone are not available. The intrauterine device (IUD) is another effective emergency contraceptive, and can be kept for ongoing contraception.

Six studies comprising a total of more than 8,000 women who used the levonorgestrel-only regimen calculated prevented fractions ranging from 60% to 94% (20). Similarly eight studies including a total of more than 3,800 women who used the combined regimen yielded prevented fractions ranging from 56% to 89%; a meta-analysis of pooled data from these studies concluded that the regimen prevents at least 74% of expected pregnancies (19). Other data suggest that the levonorgestrel-only regimen is more effective than the combined regimen and has reduced side effects. The first of two randomized trials that directly compared the two regimens found no statistically significant difference in efficacy between failure rates of the levonorgestrel-only regimen and the combined regimen (2.4% versus 2.7%, respectively). However, a second larger trial reported that the levonorgestrel-only regimen was significantly more effective for preventing pregnancy than the combined regimen (85% versus 57%, respectively) (19). Estimates based on combined data from these two studies show a reduced relative risk of pregnancy (0.51, 95% confidence interval, 0.31-.083) with the levonorgestrel-only regimen is preferred to the combined estrogen-progestin regimen, if available. Multiple randomized-controlled trials have failed to demonstrate a reduction in unintended pregnancy or abortion with increased access to EC. These data highlight the importance of counseling patients about the appropriate use of EC as an episodic intervention rather than an effective long-term method.

Side Effects

No deaths or serious complications have been causally linked to EC. Short-term side effects include the following:

Nausea and vomiting -- The levonorgestrel-only regimen is associated with significantly lower incidences of nausea and vomiting than the combined regimen. Nausea and vomiting, respectively, occur in approximately 18% and 4% of women using levonorgestrel-only EC, and in approximately 43% and 16% of women using the combined regimen (20). The incidence of nausea and vomiting is low with the levonorgestrel-only regimen, prophylactic antiemetics are not necessary. With combined regimen, antiemetic pretreatment may be beneficial because of incidence of nausea to be reported 30-60% (21). A single dose of an antiemetic taken 1 hour before the first dose of EC has been shown to decrease the incidence or severity of nausea (21). Taking EC with food does not appear to affect the risk of nausea. Many experts recommend that the EC dose should be repeated if vomiting occurs within 2 hours of taking an EC dose. If severe vomiting occurs, EC may be administered vaginally. Studies of vaginally administered combined oral contraceptive pills suggest that the hormones are effectively absorbed through the vaginal epithelium (22).

Irregular bleeding -- After EC use, the menstrual period usually occurs within 1 week before or after the expected time. Some patients experience irregular bleeding or spotting in the week or month after treatment; one trial of the levonorgestrel-only regimen found that 16% of women reported non-menstrual bleeding in the first week of use (23). If EC is taken earlier in the cycle, it is more likely that a women will experience bleeding before the expected menses. Irregular bleeding associated with EC resolves without treatment.

Other side effects -- Some patients have reported experiencing short-term side effects, such as breast tenderness, abdominal pain, dizziness, headache, and fatigue (19).

Safety of Emergency Contraception with Repeated Use

The safety of EC has been extensively studied and is well established. However, concern persists about whether their use increases the risk of ectopic pregnancy if treatment fails. In this study (27) the findings were, the rate of ectopic pregnancy when treatment with EC pills fails does not exceed the rate observed in the general population. Because EC are effective in lowering the risk of pregnancy, their use will reduce the chance that an act of intercourse will result in ectopic pregnancy. Data are not available on the safety of current regimens of EC if used frequently over a long period. However, EC may be used more than once, even within the same menstrual cycle. Information about other forms of contraception and counseling about how to avoid future contraceptive failures should be made available to women who use EC, especially those who use it repeatedly. EC is less effective than most other available methods for long-term contraception. In addition, continued use would result in exposure to higher total levels of hormones than those of either combined or progestin-only oral contraceptives, and frequent use also would result in more side effects, including menstrual irregularities. Therefore, EC should not be used as a long-term contraceptive (19).

Follow-up after Emergency Contraception

No scheduled follow-up is required after use of EC. However, the woman should be advised that if her menstrual period is delayed by a week or more, she should consider the possibility that she may be pregnant and seek clinical evaluation. A woman also should seek follow-up care for persistent irregular bleeding or lower abdominal pain because these symptoms could indicate spontaneous abortion or an ectopic pregnancy. Women also should be advised about available resources if they need ongoing contraceptive or other services, such as testing for sexually transmitted diseases, at the time EC is provided or at some convenient time thereafter.

Ulipristal Acetate: 5-Day Emergency Contraceptive

The U.S. FDA approved ulipristal acetate in August 2010 as EC. This compound in USA is marketed as ella by Watson Pharmaceutical. This new EC has been approved for use up to 5 days after unprotected intercourse. The currently available levonorgestrel ECs are approved for up to 72 hours or 3 days after unprotected sex. Ulipristal acetate is a selective progesterone receptor modulator (28). These molecules bind to the progesterone receptor, causing effects in the target organ by interfering with progesterone receptor-mediated DNA transcription. The selective progesterone receptor modulators have both agonist and antagonist effects, with a range of activities across the hundreds of compounds under investigation. Ulipristal acetate is a prescription product. ella (ulipristal acetate tablet 30 mg) can be taken at any time during the menstrual cycle. However, the ability to delay ovulation depends on when it is taken.

Dosage and Administration: 30 mg tablet -- one tablet taken orally as soon as possible, within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure. The tablet can be taken with or without food. In US it is available by prescription only.

Mechanism of action: Ulipristal acetate appears to prevent pregnancy by blocking or delaying the luteinizing hormone (LH) surge and follicular rupture when ingested before ovulation. There may also be a delay in maturation of the endometrium, which may interfere with implantation. It is believed that the primary mechanism of action of ulipristal acetate is the blocking or delaying of ovulation. Some patients and providers may be opposed to use of ulipristal acetate due to the possible inhibition of implantation. Given that ovulation sometimes occurs despite consistent use of oral contraceptives, it is likely that some embryos are unable to implant because of the endometrial effects among oral contraceptive users. It effectively delays ovulation for up to 5 days, which is also the length of time that sperm can live in the female genital tract (30).

Effectiveness: Both ulipristal acetate and levonorgestrel EC reduce the risk of unintended pregnancy. In one trial (29), ulipristal acetate was associated with an unintended pregnancy rate of 1.8% compared to an expected rate of 5.5%. Patients treated with levonorgestrel experienced 2.6% unintended pregnancies compared to 5.4% expected. Randomized trials organized as non-inferiority comparisons have been combined for meta-analysis (29). Overall, it appears that ulipristal acetate is more effective than levonorgestrel for EC (31). The timing of the dose of the EC makes a difference in its effectiveness.

Safety information: The most common side effects of ulipristal acetate tablets include headache (18%), abdominal pain (12%), nausea (12%), dysmenorrhea (9%), fatigue (6%), and dizziness (5%). It is contraindicated in women with a known or suspected pregnancy, and should not replace a regular method of contraception. Repeated use of ulipristal acetate within the same menstrual cycle is not recommended. It is not indicated for termination of an existing pregnancy. Women who become pregnant or complain of lower abdominal pain after taking the medication should be evaluated for ectopic pregnancy. It may alter the next expected menses. If menses is delayed beyond 1 week, pregnancy should be ruled out. A rapid return of fertility is likely following treatment; therefore, routine contraception should be continued or initiated as soon as possible to ensure ongoing prevention of pregnancy. It does not protect against sexually transmitted diseases/HIV.

Future Possibilities

Mifepristone -- also known as RU-486 is a progesterone and glucocorticoid receptor antagonist that has been shown to be effective as post-coital EC. In two randomized trials, it has shown fewer side effects than the standard Yuzpe regimen and equal efficacy to the levonorgestrel regimen (23). In an earlier dose-finding randomized trial, the World Health Organization (WHO) showed that mifepristone at 600 mg, 50 mg, or 10 mg equally prevented pregnancy postcoitally when taken within 5 days after intercourse. The women in the group using mifepristone 10 mg had significantly less menstrual irregularity than did those in the higher-dose groups (P(26).

Gestrinone -- also known as R2323 is a 19-nortestosterone derivative with antiprogestagenic, antiestrogenic and antigonadotropic properties. It is used most commonly for the treatment of endometriosis. It is also an effective contraceptive agent. Weekly administration of 2.5 mg gestrinone as a contraceptive to 181 women for 2 to 44 months (2,971 total women-months of use) demonstrated a typical-use failure rate of 7.3%. When given within 72 hours of unprotected coitus, 5 mg gestrinone was 88.9% effective against unwanted pregnancy (25). When administered as an EC, gestrinone is thought to inhibit blastocyst implantation. In this study (26) comparison of the efficacy of gestrinone with that of mifepristone for EC was done and the findings were -- the effectiveness of 10 mg gestrinone is not significantly different from 10 mg mifepristone as an emergency contraceptive method. The findings of the present study suggest that gestrinone is safe to use for EC; however, larger studies are needed to assess further the extent to which gestrinone can protect postcoitally against unwanted pregnancy and how it may compare with the more widely available levonorgestrel regimen.

Levonorgestrel is a contraceptive hormone that has shown similar efficacy to mifepristone as EC (23). Additionally, its post-coital regimen has been simplified into a single 1.5-mg dose and is approved and registered in more than 100 countries. However, some evidence suggests that levonorgestrel may be less effective after a 48-hour delay in treatment (24). Sustained effectiveness would be important, particularly in low-resource areas where transportation to medical facilities that may administer EC is often limited. A head-to-head trial is necessary to determine whether gestrinone has benefits over levonorgestrel regarding treatment delay.

Summary

In emergency contraception (EC) a drug or IUD is used to prevent pregnancy shortly after unprotected intercourse. Except for some Western-European countries and China, EC is largely under-utilized worldwide. In many developing countries lack of access to emergency contraception may subject women to unsafe abortions, which contribute significantly to maternal mortality and morbidity. Currently, several interventions (IUD, the Yuzpe regimen, levonorgestrel, mifepristone, danazol and some combination regimens) are available for emergency contraception. Information on the comparative efficacy, safety and convenience of these methods is crucial for reproductive health care providers and the women they serve. Information regarding long-term effective methods should be made available whenever a woman requests EC. Use of highly effective long-acting reversible methods should be encouraged in appropriate patients. To reduce the chance of nausea with the combined estrogen-progestin regimen, an antiemetic agent may be taken 1 hour before the first EC dose. Treatment with EC should be initiated as soon as possible after unprotected or inadequately protected intercourse to maximize efficacy. No clinician examination or pregnancy testing is necessary before provision or prescription of EC. EC may be used more than once, even within the same menstrual cycle and to maximize effectiveness. Women should be educated about the availability of EC. EC is not 100% effective. We can reduce the rate of unintended pregnancies with provision of ECs to our patients, preferably before it is intended. The new product offers improved effectiveness, larger windows of treatment opportunities, and a reminder to physicians to educate our patients about EC and provide them the information and resources to control their reproductive destinies.